CN107406463A - 生物分子共轭物 - Google Patents
生物分子共轭物 Download PDFInfo
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- CN107406463A CN107406463A CN201580074962.4A CN201580074962A CN107406463A CN 107406463 A CN107406463 A CN 107406463A CN 201580074962 A CN201580074962 A CN 201580074962A CN 107406463 A CN107406463 A CN 107406463A
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- radical
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- alkyl
- aryl
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- 150000001413 amino acids Chemical class 0.000 claims abstract description 85
- 238000000034 method Methods 0.000 claims abstract description 52
- 239000011230 binding agent Substances 0.000 claims abstract description 26
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims abstract description 24
- 229960000846 camphor Drugs 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- -1 poly- ethyleneoxy group Chemical group 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 47
- 239000000126 substance Substances 0.000 claims description 40
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 31
- 150000001345 alkine derivatives Chemical group 0.000 claims description 28
- 238000000926 separation method Methods 0.000 claims description 27
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical group C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000002837 carbocyclic group Chemical group 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 230000021615 conjugation Effects 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 229920001184 polypeptide Polymers 0.000 claims description 11
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 11
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 10
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000006738 (C6-C20) heteroaryl group Chemical group 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 108010016626 Dipeptides Proteins 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 3
- 125000002009 alkene group Chemical group 0.000 claims 2
- 231100000599 cytotoxic agent Toxicity 0.000 abstract description 26
- 229940127089 cytotoxic agent Drugs 0.000 abstract description 24
- 239000002254 cytotoxic agent Substances 0.000 abstract description 24
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- 235000001014 amino acid Nutrition 0.000 description 77
- 239000002585 base Substances 0.000 description 75
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- XXRGLCKZBCIEKO-DLMDZQPMSA-N azocine Chemical compound C/1=C/C=C\N=C/C=C\1 XXRGLCKZBCIEKO-DLMDZQPMSA-N 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 150000002148 esters Chemical class 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 235000018102 proteins Nutrition 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 108090000623 proteins and genes Proteins 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 239000000376 reactant Substances 0.000 description 22
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- 150000001336 alkenes Chemical class 0.000 description 19
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- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 18
- 239000000463 material Substances 0.000 description 18
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- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical class CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 238000006356 dehydrogenation reaction Methods 0.000 description 16
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- 125000005605 benzo group Chemical group 0.000 description 15
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- 239000000611 antibody drug conjugate Substances 0.000 description 13
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- 229910052786 argon Inorganic materials 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- 125000005647 linker group Chemical group 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 10
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
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- 239000011734 sodium Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 108020004566 Transfer RNA Proteins 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
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- 238000010828 elution Methods 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 230000014616 translation Effects 0.000 description 7
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 6
- 150000001540 azides Chemical group 0.000 description 6
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- 229940017219 methyl propionate Drugs 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
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- 235000011152 sodium sulphate Nutrition 0.000 description 5
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 3
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- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 3
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
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CN202210366853.1A CN114656483A (zh) | 2014-12-04 | 2015-12-03 | 生物分子共轭物 |
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US (1) | US10335495B2 (de) |
EP (3) | EP3903826B1 (de) |
JP (1) | JP2018502067A (de) |
KR (2) | KR20230144660A (de) |
CN (2) | CN107406463A (de) |
AU (1) | AU2015358367B2 (de) |
BR (1) | BR112017011773A2 (de) |
CA (2) | CA2969584C (de) |
EA (1) | EA039794B1 (de) |
IL (2) | IL252618B (de) |
MX (2) | MX2017007218A (de) |
SG (2) | SG11201704487XA (de) |
WO (1) | WO2016090157A1 (de) |
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CN107080751A (zh) * | 2017-04-27 | 2017-08-22 | 皖西学院 | 一种治疗增生性骨关节病的西药组合物及其应用 |
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JP7128121B2 (ja) | 2016-06-28 | 2022-08-30 | ヴェンタナ メディカル システムズ, インク. | Ihc及びishアッセイにおけるシグナル増幅のためのクリックケミストリーの応用 |
KR20190126314A (ko) * | 2017-02-10 | 2019-11-11 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | 암-선택적 표지화 및 표적화를 위한 트리거 활성화 가능한 당 접합체 |
JP2020529427A (ja) | 2017-08-04 | 2020-10-08 | バイスクルテクス・リミテッド | Cd137に対して特異的な二環式ペプチドリガンド |
WO2019118314A2 (en) * | 2017-12-13 | 2019-06-20 | Merck Sharp & Dohme Corp. | Scintillation proximity assay system comprising mutant dehalogenase |
EP3976112A1 (de) * | 2019-06-03 | 2022-04-06 | Synaffix B.V. | Auf acetal basierende spaltbare linker |
KR20230074119A (ko) | 2020-08-03 | 2023-05-26 | 바이사이클티엑스 리미티드 | 펩타이드 기반 링커 |
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- 2015-12-03 CN CN202210366853.1A patent/CN114656483A/zh active Pending
- 2015-12-03 EP EP21167338.9A patent/EP3903826B1/de active Active
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- 2015-12-03 KR KR1020177018256A patent/KR20170125799A/ko not_active IP Right Cessation
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CN107080751A (zh) * | 2017-04-27 | 2017-08-22 | 皖西学院 | 一种治疗增生性骨关节病的西药组合物及其应用 |
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NZ767670A (en) | 2024-01-26 |
IL252618A0 (en) | 2017-08-31 |
AU2015358367A1 (en) | 2017-07-13 |
MX2017007218A (es) | 2018-02-21 |
EA201791024A1 (ru) | 2017-11-30 |
EP3903826B1 (de) | 2024-05-08 |
BR112017011773A2 (pt) | 2018-02-20 |
CN114656483A (zh) | 2022-06-24 |
IL289802A (en) | 2022-03-01 |
JP2018502067A (ja) | 2018-01-25 |
EP3226910A1 (de) | 2017-10-11 |
IL252618B (en) | 2022-04-01 |
EP4289483A2 (de) | 2023-12-13 |
NZ732624A (en) | 2024-01-26 |
US20170360952A1 (en) | 2017-12-21 |
EP4289483A3 (de) | 2024-02-28 |
CA2969584A1 (en) | 2016-06-09 |
KR20170125799A (ko) | 2017-11-15 |
MX2022003952A (es) | 2022-05-02 |
KR20230144660A (ko) | 2023-10-16 |
AU2015358367B2 (en) | 2020-07-02 |
SG11201704487XA (en) | 2017-06-29 |
WO2016090157A1 (en) | 2016-06-09 |
CA3184805A1 (en) | 2016-06-09 |
EA039794B1 (ru) | 2022-03-15 |
SG10202008302XA (en) | 2020-10-29 |
CA2969584C (en) | 2023-03-14 |
US10335495B2 (en) | 2019-07-02 |
EP3903826A1 (de) | 2021-11-03 |
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